Rhinitis is a worldwide health problem associated with nasal inflammation and characterized by symptoms of congestion, rhinorrhea, sneezing and itching. Allergic rhinitis is the most common form of rhinitis and affects up to 30% of adults and 40% of children in the United States. Symptoms of both allergic as well as non-allergic types of rhinitis can significantly impair patients' quality of life. Moreover, allergic rhinitis often coexists with other atopic conditions, such as asthma, sinusitis and sleep apnea. Rhinitis is induced by overstimulation of parasympathetic innervation of the nasal mucosal tissue via release of acetylcholine and inflammatory mediators such as vasoactive intestinal peptide (VIP). Pharmacologic therapy (e.g., anti-histamines, decongestants, corticosteroids, anti-cholinergics, etc.) and in the case of allergic rhinitis, allergic immunotherapy, require either frequent (one or more times per day) administration often with side effects or a long-term process of desensitization with limited effectiveness for many patients.
Botulinum toxin type A is obtained from serotype A of Clostridium botulinum. Botulinum toxin type A acts to block the release of acetycholine from the presynaptic nerve terminal with consequent induction of muscular paralysis. Based on this anti-cholinergic activity, botulinum toxin type A has been used widely in the treatment of muscle spasticity disorders, and for the cosmetic treatment of frown lines and wrinkles. In addition to these applications in the neuromuscular system, botulinum toxin type A blocks parasympathetic cholinergic transmission and has been used for treatment of glandular hypersecretory disorders, such as hyperhidrosis, Frey's syndrome, sialorrhea, epiphora, rhinorrhea, and sialadenitis. It has also been shown that botulinum toxin type A can be used to suppress electrically stimulated rhinorrhea in a dog model, which is consistent with recent reports demonstrating the effect of muscarinic cholinergic agents on canine nasal veins. Subsequent studies in animal models and in human patients with different types of rhinitis demonstrated that local application of botulinum toxin type A effectively reduced rhinitis symptoms. In humans, one botulinum toxin type A treatment injected directly into the nasal turbinates significantly reduced rhinorrhoea for four weeks (Kim K S, Kim S S, Yoon J H et al. The effect of botulinum toxin type A injection for intrinsic rhinitis. J Laryngol Otol. 112:248-51, 1998) to eight weeks (Unal M, Sevim S, Do{hacek over (g)}u O et al. Effect of botulinum toxin type A on nasal symptoms in patients with allergic rhinitis: a double-blind, placebo-controlled clinical trial. Acta Otolaryngol. 123:1060-3, 2003), and provided better symptom relief than corticosteroid therapy for 20 weeks (Yang T Y, Jung Y G, Kim Y H et al. A comparison of the effects of botulinum toxin A and steroid injection on nasal allergy. Otolaryngol Head Neck Surg. 139:367-71, 2008). In addition, treatment of rhinitis using clostridial neurotoxins has been reported in U.S. Pat. Nos. 5,766,605; 7,494,661; 7,879,340; 8,088,360; and 8,088,361, as well as in U.S. Pre-Grant Publication Nos: 20120071395, 20110150975, 20110091505, 20110091504, 20110086072, 20110054442, 20060153876, 20060008462, and 20040248188. Some of these references report delivering topical liquid formulations containing commercially available botulinum type A complexes by saturating a sponge or gauze packing with a topical botulinum toxin formulation and inserting the sponge or gauze packing into the nasal cavity. The practical difficulties associated with this methodology raises certain procedural issues as well as safety concerns. In addition to the treatment of rhinitis, clostridial neurotoxins have been used in the treatment of sinusitis (see, e.g. U.S. Pat. No. 8,092,781, WO2011/084507). These and all other references cited herein are hereby incorporated by reference in their entirety.
Despite this early evidence of efficacy, the use of botulinum toxin type A for treating rhinitis has not been widely accepted among clinicians and patients. One reason for this is the oral toxicity of commercially available botulinum toxin formulations. Botulinum toxin type A, in its native form, exists as part of a protein complex that is produced by C. botulinum bacteria. The native protein complex contains, in addition to the botulinum toxin type A neurotoxin molecule, stabilizing hemaglutinin and non-hemaglutinin proteins (sometimes referred to as “accessory proteins”) which are capable of protecting the botulinum neurotoxin molecule from degradation in the harsh acidic environment of the stomach. Currently available commercial botulinum toxin type A formulations are made using native botulinum toxin protein complexes. Thus, in the event of accidental oral ingestion during the treatment of rhinitis, the accessory proteins will enable the botulinum toxin to be passed through the stomach to the small intestine, where it is absorbed into the bloodstream. If this occurs, systemic poisoning, paralysis, and even death result. Accordingly, treatment of rhinitis using the presently available commercial botulinum toxin formulations in topical preparations has been disfavored, even though botulinum toxin has been reported to be able to bind to mucosal epithelial cells and become trancytosed across mucosa. (See, e.g., U.S. Pat. No. 8,092,781).
While botulinum toxin has been reported to cross mucosa in the respiratory and gastrointestinal tract, botulinum toxin does not penetrate intact skin, owing to its size. See, e.g., S. Arnon et al., “Botulinum Toxin as a Biological Weapon—Medical and Public Health Management,” JAMA, Vol. 285, No. 8, p. 1059 ff. Accordingly, unlike delivering botulinum toxin to mucosa, one must take special measures to either disrupt the skin (see, e.g., U.S. Pre-Grant Publication No. 20070088248) or to enhance penetration of botulinum toxin via use of a carrier (see, e.g., U.S. Pat. No. 7,807,780, and U.S. Pre-Grant Publication Nos. 20050196414, 20070077259) when administering botulinum toxin transdermally.